FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - CRYSTALLINE ABACAVIR HYDROCHLORIDE
MONOHYDRATE AND PROCESS FOR ITS PREPARATION
2. Applicant(s)
(a) NAME : LUPIN LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : 159 CST Road, Kalina, Santacruz (East),
Mumbai-400 098, State of Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION:
The present invention relates to crystalline abacavir hydrochloride monohydrate and process for its preparation.
BACKGROUND OF THE INVENTION:
Abacavir (I) is chemically known as (1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-l-methanol. Abacavir sulfate and its combination are used in the treatment of human immunodeficiency virus (HIV) infection.

The patent EP 0349242 Bl discloses 9-substituted-2-amino purines including abacavir, process for preparation and pharmaceutical composition thereof.
The patent EP 0434450 Bl describes process for preparation of abacavir hydrochloride by reacting abacavir with IN hydrochloric acid in ethanol followed by evaporating the solution to dryness. The crude abacavir hydrochloride thus obtained was recrystallized from mixture of ethanol-ethyl acetate to give abacavir hydrochloride 0.8 hydrate.
The physical or chemical properties of a drug can vary depending on the crystalline form of the drug, and such physical and chemical properties can greatly influence a suitable dosage form of the drug, the optimization of a process for preparing the drug, and the in vivo absorption of the drug. The discovery of the most appropriate crystalline form of a drug in a procedure for developing the drug enables the development time and cost to be reduced.
SUMMARY OF THE INVENTION:
The present invention relates to crystalline abacavir hydrochloride monohydrate.

The present invention further provides a process for preparation of crystalline abacavir hydrochloride monohydrate comprising;
a) dissolving abacavir hydrochloride in aqueous C1-C4 alcoholic solvent,
b) cooling the solution, and
c) isolating the crystalline solid.
Brief description of drawings:
Figure 1: X-ray powder differactogram of crystalline abacavir hydrochloride monohydrate. Figure 2: IR spectrum of crystalline abacavir hydrochloride monohydrate. Figure 3: TGA of abacavir hydrochloride monohydrate.
DETAILED DESCRIPTION OF THE INVENTION:
In one embodiment there is provided crystalline abacavir hydrochloride monohydrate.
The characteristic peaks found in XRPD of crystalline abacavir hydrochloride monohydrate are given in the following table.
Peaks in the XRPD of crystalline abacavir hydrochloride monohydrate:

Position degree 29 (±0.2) d-spacing I/Io
(%) Position degree
29 (±0.2) d-spacing I/Io (%)
9.3 9.47 11.5 22.5 3.94 23.3
11.9 7.42 99.8 23.1 3.83 25.1
13.5 6.52 15.9 23.9 3.71 19.8
14.4 6.14 61.4 25.9 3.42 34.7
16.4 5.37 22.8 26.2 3.39 42.5
18.7 4.73 59.3 27.2 3.27 13.2
19.5 4.53 23.9 27.4 3.24 11.6
21.7 4.08 100 30.1 2.95 31.9
21.9 4.03 28.7 32.4 2.75 24.2
The XRPD of crystalline abacavir hydrochloride monohydrate is as shown in figure 1.
X ray of a single crystal of crystalline abacavir hydrochloride monohydrate shows that the distribution of its atoms in the crystalline network corresponds to the space group P 21 21 21,

characterized by the following cell parameters at temperature 298 °K: a= 8.0185 (8) Å; b=
10.9497 (16) Å; c= 18.762 (2) Å; α = β = γ = 90 °.
The crystalline abacavir hydrochloride monohydrate is characterized by an infra-red spectrum having major peaks at 3420, 3292, 3087, 1670, 1643 1404, 1217, 10.35 and 762± 5 cm-1. The IR spectrum of crystalline abacavir hydrochloride monohydrate is as shown in figure 2.
The crystalline abacavir hydrochloride monohydrate characterized by thermogravimetric analysis (TGA) showing Delta Y of 5 % which corresponds to the loss of one water molecule. The TGA of crystalline abacavir hydrochloride monohydrate is shown in figure 3.
The crystalline abacavir hydrochloride monohydrate was found to be stable at 25 ± 2 °C (60 ±5RH).
In another embodiment there is provided a process for preparation of crystalline abacavir hydrochloride monohydrate comprising;
a) dissolving abacavir hydrochloride in aqueous C1-C4 alcoholic solvent,
b) cooling the solution and
c) isolating the crystalline solid.
Abacavir hydrochloride used for crystallization in the present invention may be prepared as per method known in literature.
The C1-C4 alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol and butanol, preferably isopropanol.

The aqueous C1-C4 alcoholic solvent contains 1 to 20 % of water.
The quantity of aqueous C1-C4 alcoholic solvent is 5 to 15 times of abacavir hydrochloride.
The step (a) is carried out by heating which is in the range 40-80 °C, preferably the temperature is between 40-60 °C.
The solution is optionally filtered.
The solution is allowed to cool to ambient temperature, then allowed to cool to -10 to 15 °C,
more preferably to 0-5 °C.
Crystalline abacavir hydrochloride can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.
Experimental:
The powder X-ray diffraction spectrum was recorded at room temperature using PANalytical X'Pert PRO diffractogram with Cu Kα radiation (λ = 1.54060 Å), running at 45 kV and 40 mA.
FTIR spectrum was obtained using a Perkin Elmer Precisely Spectrum 400 instrument using KBr pellet method.
Thermogravimetric analysis (TGA) was done using Pyris-1 TGA Perkin Elmer instrument. The scans were recorded between 30 and 300 °C at a constant heating rate of 10°C/min.
The present invention is described in the following example, however it should be noted that the scope of present invention is not limited by the example.
Example
Preparation of Crystalline abacavir hydrochloride monohydrate
Abacavir hydrochloride (70 g) was added in mixture of water (70 ml) and isopropanol (700 ml). The mixture was heated to 50 °C to obtain clear solution. Cooled to 0-5 °C and stirred for 4 hours. The solid was filtered, washed with isopropanol (25 ml) and dried under vacuum. Yield: 50 g, melting point: 126.0-126.8 °C.

WE CLAIM:
Claim 1. A process for preparation of crystalline abacavir hydrochloride monohydrate comprising;
a) dissolving abacavir hydrochloride in aqueous C1-C4 alcoholic solvent,
b) cooling the solution, and
c) isolating the crystalline solid.
Claim 2. The process according to claim 1, wherein the C1-C4 alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol and n-butanol, preferably isopropanol.
Claim 3. The process according to claim 1, wherein the aqueous C1-C4 alcoholic solvent contains 1 to 20 % of water.
Claim 4. The process according to claim 1, wherein the mixture in step (a) is heated to 40 -80°C.
Claim 5. The process according to claim 1, wherein the solvent is 5-15 times of abacavir hydrochloride.
Claim 6. The process according to claim 1 wherein the mixture in step (b) is cooled to -10 to 15 °C, preferably 0-5 °C.
Claim 7. The crystalline abacavir hydrochloride monohydrate as obtained by the process according to claim 1, characterized by a powder X-ray diffraction pattern having peaks at

Position degree 2θ (±0.2) d-spacing I/Io
(%) Position degree
2θ (±0.2) d-spacing I/Io
(%)
9.3 9.47 11.5 22.5 3.94 23.3
11.9 7.42 99.8 23.1 3.83 25.1
13.5 6.52 15.9 23.9 3.71 19.8
14.4 6.14 61.4 25.9 3.42 34.7
16.4 5.37 22.8 26.2 3.39 42.5
18.7 4.73 59.3 27.2 3.27 13.2
19.5 4.53 23.9 27.4 3.24 11.6
21.7 4.08 100 30.1 2.95 31.9

21.9 4.03 28.7 32.4 2.75 24.2
Claim 8. The crystalline abacavir hydrochloride monohydrate as obtained by the process according to claim 1, characterized by a powder X-ray diffraction pattern substantially as depicted in figure 1.
Claim 9. The crystalline abacavir hydrochloride monohydrate as obtained by the process according to claim 1, characterized by an infra-red spectrum substantially as depicted in figure 2.
Claim 10. The crystalline abacavir hydrochloride monohydrate as obtained by the process according to claim 1, characterized by thermogravimetric analysis as shown in figure 3.